RU2012117719A - Induction of Pluripotent Cells - Google Patents

Induction of Pluripotent Cells Download PDF

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RU2012117719A
RU2012117719A RU2012117719/10A RU2012117719A RU2012117719A RU 2012117719 A RU2012117719 A RU 2012117719A RU 2012117719/10 A RU2012117719/10 A RU 2012117719/10A RU 2012117719 A RU2012117719 A RU 2012117719A RU 2012117719 A RU2012117719 A RU 2012117719A
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substituted
substituent
inhibitor
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Туньсянь ЛИНЬ
Шэн ДИН
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Зе Скрипс Ресеч Инститьют
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Abstract

1. Композиция, содержащаяингибитор активин-рецептороподобной киназы 5 (ALK5);ингибитор киназы MAP/ERK (MEK); иингибитор Rho-киназы (ROCK).2. Композиция по п.1, дополнительно содержащая ингибитор киназы гликогенсинтазы 3 (GSK3).3. Композиция по п.1, дополнительно содержащая ингибитор деацетилаз гистонов (HDAC).4. Композиция по п.1, отличающаяся тем, что ингибитор ALK5 представляют собой A-83-01 или SB431542.5. Композиция по п.1, отличающаяся тем, что ингибитор MEK представляет собой PD0325901.6. Композиция по п.1, отличающаяся тем, что ингибитор ROCK имеет структуру:гдеLпредставляет собой содержащий заместители или не содержащий заместители C-Cалкилен;y представляет собой целое число от 0 до 3;z представляет собой целое число от 0 до 5;X представляет собой -N=, -СН= или -CR=;Rпредставляет собой водород, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил;R, Rи Rнезависимо представляют собой -CN, -S(O)R, -NRR, -C(O)R, -NR-C(O)R, -NR-C(O)-OR, -C(O)NRR, -NRS(O)R, -OR, -S(O)NR, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил, г�1. A composition comprising an activin receptor-like kinase 5 (ALK5) inhibitor; a MAP / ERK kinase inhibitor (MEK); Rho kinase inhibitor (ROCK) .2. The composition of claim 1, further comprising a glycogen synthase 3 kinase inhibitor (GSK3). The composition of claim 1, further comprising a histone deacetylase inhibitor (HDAC). The composition of claim 1, wherein the ALK5 inhibitor is A-83-01 or SB431542.5. The composition according to claim 1, characterized in that the MEK inhibitor is PD0325901.6. The composition according to claim 1, characterized in that the ROCK inhibitor has the structure: where L is substituent or non-substituent C-Calkylene; y is an integer from 0 to 3; z is an integer from 0 to 5; X is -N =, -CH = or -CR =; R is hydrogen, substituted or unsubstituted alkyl, substituted or not substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted ate heterocycloalkyl substituted or non-substituted aryl, or substituted or non-substituted heteroaryl; R, R and R independently are —CN, —S (O) R, —NRR, —C (O) R, —NR-C (O) R, —NR — C (O) —OR, —C (O) NRR, —NRS (O) R, —OR, —S (O) NR, substituted or unsubstituted alkyl, substituted or non-substituted heteroalkyl, substituted or non-substituted cycloalkyl, substituted or non-substituted heterocycloalkyl, substituted or not amestiteli aryl, or containing substituents or substituents containing heteroaryl g

Claims (20)

1. Композиция, содержащая1. A composition comprising ингибитор активин-рецептороподобной киназы 5 (ALK5);activin receptor kinase 5 inhibitor (ALK5); ингибитор киназы MAP/ERK (MEK); иMAP / ERK kinase inhibitor (MEK); and ингибитор Rho-киназы (ROCK).Rho kinase inhibitor (ROCK). 2. Композиция по п.1, дополнительно содержащая ингибитор киназы гликогенсинтазы 3 (GSK3).2. The composition of claim 1, further comprising a glycogen synthase 3 kinase inhibitor (GSK3). 3. Композиция по п.1, дополнительно содержащая ингибитор деацетилаз гистонов (HDAC).3. The composition of claim 1, further comprising a histone deacetylase inhibitor (HDAC). 4. Композиция по п.1, отличающаяся тем, что ингибитор ALK5 представляют собой A-83-01 или SB431542.4. The composition according to claim 1, characterized in that the ALK5 inhibitor are A-83-01 or SB431542. 5. Композиция по п.1, отличающаяся тем, что ингибитор MEK представляет собой PD0325901.5. The composition according to claim 1, characterized in that the MEK inhibitor is PD0325901. 6. Композиция по п.1, отличающаяся тем, что ингибитор ROCK имеет структуру:6. The composition according to claim 1, characterized in that the ROCK inhibitor has the structure:
Figure 00000001
Figure 00000001
 гдеWhere L2 представляет собой содержащий заместители или не содержащий заместители C1-C10 алкилен;L 2 represents substituent or non-substituent C 1 -C 10 alkylene; y представляет собой целое число от 0 до 3;y is an integer from 0 to 3; z представляет собой целое число от 0 до 5;z is an integer from 0 to 5; X представляет собой -N=, -СН= или -CR5=;X is —N =, —CH = or —CR 5 =; R1 представляет собой водород, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил;R 1 is hydrogen, substituted or non-substituted alkyl, substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or containing or non-substituted heteroaryl; R3, R4 и R5 независимо представляют собой -CN, -S(O)nR6, -NR7R8, -C(O)R9, -NR10-C(O)R11, -NR12-C(O)-OR13, -C(O)NR14R15, -NR16S(O)2R17, -OR18, -S(O)2NR19, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил, где n представляет собой целое число от 0 до 2, при этом если z больше 1, две группы R3 возможно соединены друг с другом с образованием содержащего заместители или не содержащего заместители циклоалкила, содержащего заместители или не содержащего заместители гетероциклоалкила, содержащего заместители или не содержащего заместители арила, или содержащего заместители или не содержащего заместители гетероарила; иR 3 , R 4 and R 5 independently represent —CN, —S (O) n R 6 , —NR 7 R 8 , —C (O) R 9 , —NR 10 —C (O) R 11 , —NR 12 -C (O) -OR 13 , -C (O) NR 14 R 15 , -NR 16 S (O) 2 R 17 , -OR 18 , -S (O) 2 NR 19 , with or without substituents alkyl substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or substituted or not substituted heteroaryl, where n represents an integer from 0 to 2, wherein if z is greater than 1, two R 3 groups may be joined together to form substituent or non-substituent cycloalkyl, substituent or non-substituent heterocycloalkyl, substituent or non-substituent aryl, or containing substituents or non-substituted heteroaryl; and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18, R19 независимо представляют собой водород, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, не содержащий заместители циклоалкил, содержащий заместители или не содержащий замести гели гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил;R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , R 19 independently represent hydrogen containing substituents or not alkyl containing substituents, substituent or non-substituent heteroalkyl, substituent cycloalkyl, substituent or non-substituting heterocycloalkyl gels, substituent or substituent aryl, or substituent or substituent heteroaryl; или его рацемат, диастереомер, таутомер или геометрический изомер, или его фармацевтически приемлемая соль.or its racemate, diastereomer, tautomer or geometric isomer, or a pharmaceutically acceptable salt thereof. 7. Ингибитор ROCK по п.6, где7. The ROCK inhibitor according to claim 6, where L2 представляет собой метилен;L 2 represents methylene; X представляет собой N= или СН=;X represents N = or CH =; R1 представляет собой водород; илиR 1 represents hydrogen; or y и z равны 0.y and z are 0. 8. Ингибитор ROCK по п.6, где8. The ROCK inhibitor according to claim 6, where L2 представляет собой метилен;L 2 represents methylene; X представляет собой N= или СН=;X represents N = or CH =; R1 представляет собой водород; иR 1 represents hydrogen; and y и z равны 0.y and z are 0. 9. Ингибитор ROCK по п.6, отличающийся тем, что указанный ингибитор ROCK имеет структуру:9. The ROCK inhibitor according to claim 6, characterized in that said ROCK inhibitor has the structure:
Figure 00000002
Figure 00000002
Figure 00000003
или
Figure 00000003
or
Figure 00000004
.
Figure 00000004
. 10. Композиция по п.1, содержащая один или более типов клеток млекопитающего.10. The composition according to claim 1, containing one or more types of mammalian cells. 11. Смесь, содержащая11. The mixture containing один или более типов клеток млекопитающего;one or more types of mammalian cells; ингибитор ALK5;ALK5 inhibitor; ингибитор МЕК; иMEK inhibitor; and ингибитор ROCK.ROCK inhibitor. 12. Смесь по п.11, отличающаяся тем, что клетки млекопитающего включают неплюрипотентные клетки.12. The mixture according to claim 11, characterized in that the mammalian cells include non-pluripotent cells. 13. Смесь по п.11, дополнительно содержащая ингибитор киназы гликогенсинтазы 3 (GSK3).13. The mixture according to claim 11, further comprising a glycogen synthase 3 kinase inhibitor (GSK3). 14. Смесь по п.11, дополнительно содержащая ингибитор деацетилаз гистонов (HDAC).14. The mixture of claim 11, further comprising a histone deacetylase inhibitor (HDAC). 15. Способ индуцирования неплюрипотентных клеток млекопитающих с получением индуцированных плюрипотентных стволовых клеток, включающий:15. A method of inducing non-pluripotent mammalian cells to produce induced pluripotent stem cells, comprising: введение по меньшей мере одного фактора транскрипции, выбранного из группы, состоящей из: Oct-3/4, Klf4, Sox2 и c-Myc, в неплюрипотентные клетки; иthe introduction of at least one transcription factor selected from the group consisting of: Oct-3/4, Klf4, Sox2 and c-Myc, in non-pluripotent cells; and приведение неплюрипотентных клеток в контакт с ингибитором ALK5, ингибитором MEK и ингибитором ROCK;bringing non-pluripotent cells into contact with an ALK5 inhibitor, a MEK inhibitor, and a ROCK inhibitor; в условиях, достаточных для индуцирования плюрипотентных стволовых клеток.under conditions sufficient to induce pluripotent stem cells. 16. Способ по п.15, отличающийся тем, что введение по меньшей мере одного фактора транскрипции в неплюрипотентные клетки включает введение полинуклеотида, кодирующего указанный по меньшей мере один фактор транскрипции, в неплюрипотентные клетки.16. The method according to clause 15, wherein the introduction of at least one transcription factor into non-pluripotent cells includes the introduction of a polynucleotide encoding the specified at least one transcription factor into non-pluripotent cells. 17. Способ по п.15, отличающийся тем, что введение по меньшей мере одного фактора транскрипции в неплюрипотентные клетки включает приведение неплюрипотентных клеток в контакт с полипептидом, содержащим аминокислотную последовательность указанного по меньшей мере одного полипептида фактора транскрипции.17. The method according to clause 15, wherein the introduction of at least one transcription factor into non-pluripotent cells includes contacting the non-pluripotent cells with a polypeptide containing the amino acid sequence of the specified at least one transcription factor polypeptide. 18. Способ по п.15, дополнительно включающий приведение неплюрипотентных клеток в контакт с ингибитором GSK3.18. The method according to clause 15, further comprising bringing non-pluripotent cells into contact with a GSK3 inhibitor. 19. Способ по п.15, дополнительно включающий приведение неплюрипотентных клеток в контакт с ингибитором HDAC.19. The method according to clause 15, further comprising bringing non-pluripotent cells into contact with an HDAC inhibitor. 20. Способ по п.15, отличающийся тем, что ингибитор ROCK имеет структуру:20. The method according to clause 15, wherein the ROCK inhibitor has the structure:
Figure 00000001
Figure 00000001
 гдеWhere L2 представляет собой содержащий заместители или не содержащий заместители C1-C10 алкилен;L 2 represents substituent or non-substituent C 1 -C 10 alkylene; y представляет собой целое число от 0 до 3;y is an integer from 0 to 3; z представляет собой целое число от 0 до 5;z is an integer from 0 to 5; X представляет собой -N=, -СН= или -CR5=;X is —N =, —CH = or —CR 5 =; R1 представляет собой водород, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил;R 1 is hydrogen, substituted or non-substituted alkyl, substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or containing or non-substituted heteroaryl; R3, R4 и R5 независимо представляют собой -CN, -S(O)nR6, -NR7R8, -C(O)R9, -NR10-C(O)R11, -NR12-C(O)-OR13, -C(O)NR14R15, -NR16S(O)2R17, -OR18, -S(O)2NR19, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, содержащий заместители или не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил, где n представляет собой целое число от 0 до 2, при этом если z больше 1, две группы R3 возможно соединены друг с другом с образованием содержащего заместители или не содержащего заместители циклоалкила, содержащего заместители или не содержащего заместители гетероциклоалкила, содержащего заместители или не содержащего заместители арила, или содержащего заместители или не содержащего заместители гетероарила; иR 3 , R 4 and R 5 independently represent —CN, —S (O) n R 6 , —NR 7 R 8 , —C (O) R 9 , —NR 10 —C (O) R 11 , —NR 12 -C (O) -OR 13 , -C (O) NR 14 R 15 , -NR 16 S (O) 2 R 17 , -OR 18 , -S (O) 2 NR 19 , with or without substituents alkyl substituted or non-substituted heteroalkyl, substituted or not substituted cycloalkyl, substituted or not substituted heterocycloalkyl, substituted or not substituted aryl, or substituted or not substituted heteroaryl, where n represents an integer from 0 to 2, wherein if z is greater than 1, two R 3 groups may be joined together to form substituent or non-substituent cycloalkyl, substituent or non-substituent heterocycloalkyl, substituent or non-substituent aryl, or containing substituents or non-substituted heteroaryl; and R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, R17, R18 и R19 независимо представляют собой водород, содержащий заместители или не содержащий заместители алкил, содержащий заместители или не содержащий заместители гетероалкил, не содержащий заместители циклоалкил, содержащий заместители или не содержащий заместители гетероциклоалкил, содержащий заместители или не содержащий заместители арил, или содержащий заместители или не содержащий заместители гетероарил;R 6 , R 7 , R 8 , R 9 , R 10 , R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 and R 19 independently represent hydrogen containing substituents or not alkyl containing substituents, substituents or substituents heteroalkyl, substituents cycloalkyl, substituents or substituents heterocycloalkyl, substituents or substituents aryl, or substituents or substituents heteroaryl; или его рацемат, диастереомер, таутомер или геометрический изомер, или его фармацевтически приемлемая соль. or its racemate, diastereomer, tautomer or geometric isomer, or a pharmaceutically acceptable salt thereof.
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EP2488630A4 (en) 2013-06-26
EP2488630A1 (en) 2012-08-22
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